The Initial 96 Hours of Invasive Pulmonary Aspergillosis: Histopathology,Comparative Kinetics of Galactomannan and (1→3)-β-d-Glucan,and Consequences of Delayed Antifungal Therapy

Acute invasive pulmonary aspergillosis is a rapidly progressive and frequently lethal infection. Relatively little is known about early events in the pathogenesis and relationship between the cell wall biomarkers galactomannan and (1→3)-β-d-glucan. The consequences of delayed antifungal therapy are also poorly defined. A persistently neutropenic rabbit model of invasive pulmonary aspergillosis was used to describe the histopathology of early invasive pulmonary aspergillosis and the kinetics of galactomannan and (1→3)-β-d-glucan. The time course of both molecules was mathematically modeled by using a population methodology, and Monte Carlo simulations were performed. The effect of progressive delay in the administration of amphotericin B deoxycholate 1 mg/kg at 24, 48, 72, and 96 h postinoculation on fungal burden, lung weight, pulmonary infarct score, and survival was determined. Histopathology showed phagocytosis of conidia by pulmonary alveolar macrophages at 4 h postinoculation. At 12 to 24 h, there was a progressive focal inflammatory response with conidial germination and hyphal extension. Subsequently, hyphae invaded into the contiguous lung. Galactomannan and (1→3)-β-d-glucan had similar trajectories, and both exhibited considerable interindividual variability, which was reflected in Monte Carlo simulations. Concentrations of both molecules began to rise <24 h postinoculation before pulmonary hemorrhagic infarction was present. Delays of 72 and 96 h in the administration of amphotericin B resulted in fungal burdens and lung weights that were indistinguishable from those of controls, respectively. Galactomannan and (1→3)-β-d-glucan have similar kinetics and are comparable biomarkers of early invasive pulmonary aspergillosis. Antifungal treatment at ≥48 h postinoculation is associated with suboptimal therapeutic outcomes.Acute invasive pulmonary aspergillosis is a leading cause of morbidity and mortality in immunocompromised patients. There have been considerable efforts to improve the diagnostic accuracy and therapeutic outcomes associated with this frequently lethal infection. A better understanding of the relationship of clinically relevant biomarkers and the pathogenesis of invasive pulmonary aspergillosis would facilitate further development of strategies to identify and treat patients at the earliest possible time.Galactomannan and (1→3)-β-d-glucan are complex carbohydrate cell wall molecules produced by Aspergillus spp. The diagnostic and prognostic value of these biomarkers in experimental models and humans is relatively well characterized (7, 12, 17, 18, 23). Despite this, there is little understanding of the relationship of the time course of galactomannan and (1→3)-β-d-glucan to early events in the pathogenesis of invasive pulmonary aspergillosis, and no studies that have rigorously compared their kinetics in laboratory animals or humans.Recently, we described the kinetics of galactomannan in persistently neutropenic rabbits with early invasive pulmonary aspergillosis (12). In the present study, we extend our previous findings by defining the critical histopathological events in early invasive pulmonary aspergillosis and further characterize and compare the kinetics of the circulating fungal antigens galactomannan and (1→3)-β-d-glucan. We further explore the consequences of delayed antifungal therapy with amphotericin B deoxycholate to provide insight into the period after inoculation in which favorable therapeutic outcomes can be secured in profoundly immunocompromised hosts.     

Palliative management of refractory dyspnea in COPD

COPD is a progressive illness with worldwide impact. Patients invariably reach a point at which they require palliative interventions. Dyspnea is the most distressing symptom experienced by these patients; when not relieved by traditional COPD management strategies it is termed “refractory dyspnea” and palliative approaches are required. The focus of care shifts from prolonging survival to reducing symptoms, increasing function, and improving quality of life. Numerous pharmacological and non-pharmacological interventions can achieve these goals, though evidence supporting their use is variable. This review provides a summary of the options for the management of refractory dyspnea in COPD, outlining currently available evidence and highlighting areas for further investigation. Topics include oxygen, opioids, psychotropic drugs, inhaled furosemide, Heliox, rehabilitation, nutrition, psychosocial support, breathing techniques, and breathlessness clinics.     

A review of the tripartite model for understanding the link between anxiety and depression in youth

Although research from numerous investigations indicates that there is substantial overlap in anxiety and depressive symptoms and comorbid diagnoses in youth, these constructs can be adequately differentiated. Clark and Watson [Clark, L. A. & Watson, D., (1991). Tripartite model of anxiety and depression: Psychometric evidence and taxonomic implications. Journal of Abnormal Psychology, 100, 316-336] proposed a tripartite model to account for the symptom overlap and diagnostic comorbidity between anxiety and depression. This tripartite model posits that anxiety and depression share a common component of negative affect, but can be differentiated by low positive affect associated with depression and high physiological hyperarousal associated with anxiety. The present article reviews initial research which has supported the utility of the tripartite model for explaining the association between anxiety and depression in adult and youth samples. Following that review, more recent investigations which have called into question the applicability of the tripartite constructs for youth are presented. Finally, the paper reviews evidence suggesting that the tripartite factors may not function similarly across all anxiety and depressive disorders. This article concludes by suggesting that more research is necessary with children and adolescents in order to determine the functioning of tripartite constructs across anxiety disorders in youth.     

Body composition in patients with inflammatory bowel disease: a population-based study

OBJECTIVE: Weight loss and nutritional depletion are common features of inflammatory bowel disease. Our aim was to assess body composition in patients with Crohn's disease (CD) and ulcerative colitis (UC) and to evaluate possible differences between the patient groups and healthy subjects. METHODS: A total of 60 patients with CD, 60 patients with UC, and 60 healthy subjects were investigated. Each group consisted of 24 men and 36 women. Body composition was measured by dual x-ray absorptiometry and Z scores were obtained by comparison to age- and sex-matched normal values. RESULTS: Bone mineral content and lean body mass were significantly lower in patients with CD compared with patients with UC and healthy subjects. The body composition of CD men was more strongly affected than that of women. UC patients had significantly higher fat mass and body mass index than patients with CD and healthy subjects. There was no difference in the percentage of fat mass between the two patient groups. Corticosteroid treatment and smoking had a negative impact on bone mineral content and lean body mass in CD patients independently of each other. CONCLUSIONS: CD was associated with disturbances in body composition: both bone mineral content and lean body mass were significantly reduced, especially in men with CD. Corticosteroid therapy and smoking had a significant influence on body composition in patients with CD. When studying the effects of inflammatory bowel disease on body composition and nutritional status, patients with CD and UC should be evaluated separately.     

Bronchial response to breathing dry gas at 3.7 MPa ambient pressure

In diving, pulmonary mechanical function is limited by the increased density of the gas breathed. Breathing cold and dry gas may cause an additional increase in airways resistance. We have measured forced vital capacity, forced expired volume in 1 s (FEV₁) and forced midexpiratory flow rate (FEF_25%–75%) before and after breathing dry or humid gas at 29–32°C during a standardized exercise intensity on a cycle ergometer at an ambient pressure of 3.7 MPa. The atmosphere was a helium and oxygen mixture with a density of 6.8 kg · m^–3. Six professional saturation divers aged 26–37 years participated in the study. There were no significant differences in convective respiratory heat loss between the exposures. The mean evaporative heat loss was 67 W (range 59–89) breathing dry gas and 37 W (range 32–43) breathing humid gas, corresponding to water losses of 1.7 g · min^–1 (range 1.5–2.2) and 0.9 g · min^–1 (range 0.8–1.1), respectively. There was a significant reduction in FEV₁ of 4.6 (SD 3.6)% (P<0.05), and in FEF_25%–75% of 5.8 (SD 4.7)% (P<0.05) after breathing dry gas. There were no changes after breathing humid gas. By warming and humidifying the gas breathed in deep saturation diving bronchoconstriction may be prevented.